Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8( ) T cell-mediated airway hyperresponsiveness and inflammation

作者：Ohnishi Hiroshi; Takeda Katsuyuki; Domenico Joanne; Lucas Joseph J; Miyahara Nobuaki; Swasey Christina H; Dakhama Azzeddine; Gelfand Erwin W^*

来源：Journal of Allergy and Clinical Immunology, 2009, 123(1): 249-257.

DOI：10.1016/j.jaci.2008.10.054

• Allergy
• asthma
• effector memory T cell
• mitogen-activated protein kinase
• signal transduction

Background: Ligation of the leukotriene B-4 (LTB4) receptor I on effector memory CD8( ) T cells by LTB4 is important for the recruitment of CD8( ) T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types.
Objective: The roles of ERKs in effector CD8( ) T-cell function and on CD8( ) T cell-mediated AHR were determined.
Methods: Effector CD8( ) T cells were generated from OVA(257.264) (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8( ) T-cell function and on CD8( ) T cell-mediated AHR and allergic inflammation were examined.
Results: Pretreatment of effector CD8( ) T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB4-induced Ca2 mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8( ) T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8( ) T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment.
Conclusion: ERK1/2-dependent pathways are essential for the effector functions of CD8( ) T cells, including T(H)2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8( ) T cell-mediated AHR. (J Allergy Clin Immunol 2009;123:249-57.)

• 出版日期2009-1